The expanding repertoire of covalent warheads for drug discovery

Namrashee V Mehta; Mariam S Degani

doi:10.1016/j.drudis.2023.103799

The expanding repertoire of covalent warheads for drug discovery

Drug Discov Today. 2023 Dec;28(12):103799. doi: 10.1016/j.drudis.2023.103799. Epub 2023 Oct 13.

Authors

Namrashee V Mehta¹, Mariam S Degani²

Affiliations

¹ Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400019, Maharashtra, India. Electronic address: namrashee@gmail.com.
² Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400019, Maharashtra, India. Electronic address: ms.degani@ictmumbai.edu.in.

PMID: 37839776
DOI: 10.1016/j.drudis.2023.103799

Abstract

The reactive functionalities of drugs that engage in covalent interactions with the enzyme/receptor residue in either a reversible or an irreversible manner are called 'warheads'. Covalent warheads that were previously neglected because of safety concerns have recently gained center stage as a result of their various advantages over noncovalent drugs, including increased selectivity, increased residence time, and higher potency. With the approval of several covalent inhibitors over the past decade, research in this area has accelerated. Various strategies are being continuously developed to tune the characteristics of warheads to improve their potency and mitigate toxicity. Here, we review research progress in warhead discovery over the past 5 years to provide valuable insights for future drug discovery.

Keywords: chemical probes; covalent drug design; covalent reversible inhibitors; electrophilic warhead; irreversible inhibitors; targeted covalent inhibitors.

Publication types

Review

MeSH terms

Chemistry, Pharmaceutical*
Drug Discovery*